A P A P A Perspective o A Perspective o ti ti on the Current - PowerPoint PPT Presentation

A P A P A Perspective o A Perspective o ti ti on the Current on the Current th C th C t t Environment for A Environment for A Adaptive Clinical Adaptive Clinical p Tri Tri ials ials Robert T. O Robert T. O ’Neill, PhD ’Neill, PhD Senior Statist Senior Statist tical Advisor tical Advisor Office of Translational Office of Translational l Sciences, CDER, FDA l Sciences, CDER, FDA For presentation at the 2 nd Annual East U ser Group Meeting, Cambridge, MA ; October 12, 2012

Outline o Outline o Outline o Outline o of the talk of the talk of the talk of the talk  How did the adaptive d How did the adaptive d design initiative begin and design initiative begin and h h how did it develop with how did it develop with did it d did it d l l ith ith hi th hi th hin the regulatory hin the regulatory l t l t environment environment Promoting and guiding Promoting and guiding P P i i d d idi idi g innovation g innovation i i i i   Some concerns and curr Some concerns and curr rent climate rent climate  What have we learned What have we learned  Where are we going Where are we going Where are we going Where are we going  

http://www.fda.gov/oc/initiatives/criticalpath/

Main m Main m Main m Main m messages messages messages messages Failure rate of phase 3 confir Failure rate of phase 3 confir rmatory trials rmatory trials   Few industry case stud Few industry case stud dies diagnosing the causes dies diagnosing the causes  Desire to streamline clinical Desire to streamline clinical trials trials Desire to take advantage of n Desire to take advantage of n new science and discoveries that new science and discoveries that  are not impacting success rat are not impacting success rat tes for new treatments tes for new treatments Concern for a non sustainab Concern for a non sustainab Concern for a non sustainab Concern for a non sustainab ble model for drug development ble model for drug development ble model for drug development ble model for drug development    This is a problem for multip This is a problem for multip ple stakeholders (industry, ple stakeholders (industry, academics, regulators, patien academics, regulators, patien nts) nts)  regulatory science is n regulatory science is n not well understood or not well understood or recognized as a discipl recognized as a discipl line line

The PhRMA The PhRMA A WG with A WG with discussion discussion discussion discussion (JBS 2006) (JBS 2006) (JBS 2006) (JBS 2006)

Impact of PDU Impact of PDU FA IV (Sept. 2007) FA IV (Sept. 2007) FDA negotiated and FDA negotiated and d promised a guidance d promised a guidance on Adapt on Adapt tive Designs tive Designs

Two Regulato Two Regulato ory Guidances ory Guidances Issued (20 Issued (20 Issued (20 Issued (20 006 2010) 006 2010) 006, 2010) 006, 2010)

Philosophy of F Philosophy of F Philosophy of F Philosophy of F FDA Guidance FDA Guidance FDA Guidance FDA Guidance Understandable to a wi Understandable to a wi de audience, including de audience, including  clinicians and statisticia clinicians and statisticia clinicians and statisticia clinicians and statisticia ans, and others ans and others ans and others ans, and others  Cautionary but encoura Cautionary but encoura age use for exploratory age use for exploratory studies and for confirm studies and for confirm matory studies, if and when matory studies, if and when warranted warranted d Terminology and defini Terminology and defini itions are important: itions are important:  Seamless Phase 2 /Phase Seamless Phase 2 /Phase Seamless Phase 2 /Phase Seamless Phase 2 /Phase e 3 terminology confuses e 3 terminology confuses e 3 terminology confuses e 3 terminology confuses exploration with confirm exploration with confirm mation mation We are still learning, ex We are still learning, ex g xamples are increasing and xamples are increasing and p p g g  evolving , as is methodo evolving , as is methodo l l d d ology ology l

Definition and Definition and d concept of an d concept of an adaptive adaptive d d i i e design e design d d i i (FDA Gu (FDA Gu uidance) uidance) For the purposes of this gu For the purposes of this gu idance, an adaptive design idance, an adaptive design clinical study is defined as clinical study is defined as a study that includes a a study that includes a prospectively planned and s prospectively planned and s ti ti l l l l d d d d specified modification or specified modification ifi d ifi d difi difi ti ti or potential for modification o potential for modification o of one or more specified of one or more specified aspects of the study design aspects of the study design and hypotheses, and hypotheses, based on based on analysis of data from subjec analysis of data from subjec l l i f d t f i f d t f bj bj cts in the study cts in the study . Analyses t i th t d t i th t d . Analyses A A l l of the accumulating study d of the accumulating study d data are often performed at data are often performed at prospectively planned poin prospectively planned poin nts within the study, may nts within the study, may be performed in a b b be performed in a fully blin f f d i f ll bli d i fully blin f ll bli nded manner or in a non nded manner or in a non- d d d d i i - blinded manner blinded manner , and may, at , and may, at t an interim time point, t an interim time point, occur with or without form occur with or without form mal statistical hypothesis mal statistical hypothesis t testing (eg. decision tools). t testing (eg. decision tools). ti ti ( ( d d i i i i t t l ) l )

Some Clar Some Clar rifications rifications (FDA Gu (FDA G (FDA Gu (FDA G uidance) uidance) id id ) ) The term “prospective” The h term “prospective” here “ “ i i ” ” h here e means that the adaptation e means that the adaptation h h h h d d i i was planned (and details spe was planned (and details spe ecified) before data were ecified) before data were examined in an unblinded fo examined in an unblinded fo orm by any personnel orm by any personnel involved in planning for the involved in planning for the involved in planning for the involved in planning for the e revision. This can include e revision. This can include e revision This can include e revision This can include plans that are introduced or plans that are introduced or finalized after the study finalized after the study has commenced if confidenc has commenced if confidenc ce in the blinded state of ce in the blinded state of the personnel involved is un the personnel involved is un the personnel involved is un the personnel involved is un nequivocally maintained nequivocally maintained nequivocally maintained nequivocally maintained and documented when the m and documented when the m modification plan is modification plan is proposed. The documentatio proposed. The documentatio on that can support on that can support unequivocal assurance of bli unequivocal assurance of bli inding for the necessary inding for the necessary personnel while a study is on personnel while a study is on l l hil hil d i d i ngoing may be important ngoing may be important i i b i b i to discuss with FDA. to discuss with FDA. Chang Chang ges in study design ges in study design occurring after an interim an occurring after an interim an nalysis of unblinded nalysis of unblinded study study data and that were not prosp data and that were not prosp data and that were not prosp data and that were not prosp pectively planned are not pectively planned are not pectively planned are not pectively planned are not within the scope of this guid within the scope of this guid dance. dance.